Depletion of CD4+ T lymphocytes is a central immunological characteristic of infection with human immunodeficiency virus-type 1 (HIV-1). Although the mechanism of such CD4+ cell loss remains unclear, interactions between viral and host cell factors are thought to play an important role in the pathogenesis of HIV-1 disease. Cytokines play an important role in regulating HIV-1 replication in lymphocytes and macrophages are may contribute to HIV pathogenesis in vivo. Cytokines also have potential as immunotherapy for AIDS and HIV infection. We have continued to investigate the impact of cytokines on HIV replication in macrophages and T cells and have studied the molecular mechanisms involved in their action. We have now identified the multifunctional cytokine transforming growth factor-beta1 (TGF-beta1) as a key host factor contributing to the depletion of CD4+ T lymphocytes following HIV infection in vitro. Exposure of resting human peripheral T cells in culture to TGF-beta1 was found to increase the expression of the HIV-1 co-receptors CCR5 and CXCR4 and support both HIV-1 entry and completion of reverse transcription of viral RNA. Virus production by cells cultured in the presence of interleukin-2 (IL-2) was inhibited by TGF-beta1 and this inhibition was accompanied by a loss of T cells from the culture and an increase in CD4+ T cell apoptosis. In the presence of TGF-beta1 even infection with a non-cytopathic CCR5-dependent isolate of HIV-1 was associated with a marked increase in CD4+ T cell apoptotic death. TGF-beta1/HIV-1 induced apoptosis occurred through both caspase independent and dependent pathways. These results show that TGF-beta1 promotes the depletion of CD4+ T cells after R5 HIV-1 infection by inducing apoptosis and they suggest that TGF-beta1 might contribute to the pathogenesis of HIV-1 infection in vivo.